COPD is a heterogeneous lung condition characterized by progressive loss of lung function causing increasing breathlessness and loss of quality of life. While the predominant mechanism of lung injury in the US is cigarette smoke exposure, the condition is due to an admixture of emphysema and airways disease. This unpredictable mix of tissue pathology is indiscernible by conventional spirometric measures of lung function. This has lead to the recruitment of very large numbers of subjects into clinical studies to include the various subsets of disease. Recently, the NHLBI put forth a consensus statement specifying the need for new techniques to "phenotype" the pulmonary component of COPD, including image-based analysis. Our overall hypothesis is that airway characteristics in subjects with COPD are independent predictors of disease pathophysiology and clinical indices of lung function. Aim 1 of this application is to analyze chest CT scans from 3 independent cohorts and correlate the structural characteristics with clinical and spirometric parameters. Aim 2 involves the histologic validation of our novel CT derived metrics of airways disease defined in Aim 1. In Aim 3, our novel CT measures of airway disease will be applied to a prospectively collected cohort of subjects from the Genetic Epidemiology of COPD Investigation (1 RO1 HL089897 and 1 RO1 HL089856-01A1). In subjects enrolled locally, I will perform physiologic measures of airway inspiratory resistance, compliance and conductance using techniques pioneered at Brigham and Women's Hospital. Validation of these measures of airway disease and investigation of their interdependence with the CT assessed burden of emphysema may provide a non-invasive tool to be used as a biomarker for clinical investigation in chronic obstructive pulmonary disease. The aims of this research proposal are possible through the active collaboration of Dr. John J. Reilly, MD, a well recognized clinical investigator in COPD, Dr. Edwin Silverman MD, PhD, the national co-primary investigator of the Genetic Epidemiology of COPD Investigation and a well recognized specialist in clincial/genetics research of COPD, and Dr. Ron Kikinis, MD, an expert in quantitative image analysis and interpretation. (End of Abstract)